Providing straightforward information pertaining to drugs, drug use & drug policy. The Grey Pages promotes drug-related literacy and advocates a system of viable and tolerant drug policies. This is my personal collection of commentaries, essays, tid-bits, and other such writings on everything ranging from drug use, drug policy and drug-myths, to drug-science, addiction, human behavior, and the workings of the human brain. I started this blog with a particular focus on opioids, and over the past year have found my interest gravitate toward the intriguing, ever-changing world of designer intoxicants (i.e. "research chemicals" or "designer drugs").

Wednesday, November 30, 2011

Pharmacokinetic Chart

Reference Chart displaying oral efficacy, time to onset, average half life, plasma protein binding, and duration of effect - for several common opioids.

Sunday, November 20, 2011

Receptor Affinity & Selectivity of Common Opioid Agonists

Buprenorphine: mu partial agonist, kappa antagonist, ORL1-partial agonist

Morphine: mu agonist, delta & kappa agonist (in high doses) . 38/1 mu/kappa selectivity

Oxycodone: predominant mu agonist, delta & kappa agonist (very low affinity) . 135/1 mu/kappa selectivity

Hydrocodone: mu agonist, delta & kappa agonist (in high doses) . 68/1 mu/kappa selectivity

Hydromorphone: mu agonist, delta & kappa agonist (in high doses) . 26/1 mu/kappa selectivity

Oxymorphone: mu agonist, delta & kappa agonist (in high doses) . 82/1 mu/kappa selectivity

Levorphanol: mu agonist, kappa agonist, delta agonist, NMDA antagonist, 5HT & NE reuptake inhibitor . no selectivity

Methadone: predominant mu agonist, NMDA antagonist, nACh antagonist, delta & kappa agonist (very low affinity) . 493/1 mu/kappa selectivity

Fentanyl: predominant mu agonist, delta & kappa agonist (very low affinity) . 121/1 mu/kappa selectivity

Etorphine: mu agonist, kappa agonist, delta agonist . no selectivity

Codeine: mu agonist, delta & kappa agonist (in high doses) . 35/1 mu/kappa selectivity

Tramadol: selective mu agonist (very low affinity), 5HT & NE reuptake inhibitor . high selectivity

Ranked Mu-Receptor Affinities of Various Opioids:

A series of binding assays was performed to rank the relative MOR binding affinies of common opioids - The drugs have been ranked by 3 groups - Higher numbers indicate a weaker affinity, while lower numbers indicate strong affinity

NM= nanomolars MM= micromolars

MOR Binding Potency

100nm or greater (weak) - Tramadol, Codeine, Pethidine, Propoxyphene, Pentazocine

1 to 100nm (moderate) - hydrocododone, oxycodone, Methadone, fentanyl, morphine

1nm or lower (strong) - levorphanol, oxymorphone, hydromorphone, buprenorphine, sufentanil

A Review of the Opioid Receptor System

MOR - Micro Receptor (OP3)

Locations: brainstem (medulla, LC), medial thalamus, lymbic circuitry (NA, VTA, amygdala), PAG, anterior cingulate, cerebral cortex, dorsal spinal cord & SG, and GI tract

Ligands: endomorphin, enkephalin, DAMGO)

u1 - analgesia in the brain (supraspinal analgesia), euphoria, excitement, mesolimbic reward, psycho-dependence

u2 - analgesia in the spine (spinal analgesia), sedation, anxiolysis, respiratory depression, constipation, itching, physical dependence, tolerance

u3 - unknown function

2 subtypes of the mu receptor (MOR) have been characterized. Mu-1 receptors affect emotional state and emotional response (functions of mood), wherease mu-2 receptors affect arousal, physical dependence, and respiration (autonomic functions). Both subtypes mediate analgesia (pain relief), though perhaps through different locations (brain vs spinal cord). We can assume that mu-1 receptors are predominantly active in forebrain structures such as the limbic areas, while mu-2 receptors primarily affect activity in lower structures such as the hypothalamus, brainstem, and spinal cord, which modulate function at a more basal level.

The presence of two MOR subtypes was deducted from research which dissociated supraspinal morphine analgesia from respiratory depression and constipation, through selective application of the mu antagonist naloxonazine.

A 3rd subtype of mu receptor has been theorized based on the analgesia produced by morphine 6-substituted analogues in mu1 and 2 knockout subjects. This third subtype interacts with opioid alkaloid compounds and not opioid peptides, and has been referred to as the morphine-6-glucuronide receptor; only certain compounds are believed to interact with this subtype - specifically, morphine analogues with C-6 substitutions such as morphine-6-glucuronide, 6-acetylmorphine, heterocodeine, and possibly fentanyl.

KOR - Kappa Receptor (OP2)

Locations: brainstem, hypothalamus, dorsal spinal cord & SG, PAG, claustrum, limbic circuitry

Ligands: dynorphin, enadoline, ketocyclazocine

Associated with spinal analgesia, dysphoria, aversion, miosis, sedation, diuresis (increased urination), psychotomimesis, anti-itching, counteraction of mu-agonist effects, anti-addictive effect, dopamine inhibition, mu & dopamine receptor upregulation

At least 2 subtypes of kappa receptor have been characterized. Kappa is the endogenous dynorphin receptor. KOR is involved in spinal analgesia, and counteraction to many mu-mediated effects (namely euphoria and addiction).

DOR - Delta Receptor (OP1)

Locations: neocortex, caudate nucleus, putamen, amygdala, olfactory bulbs, pons, dorsal spinal cord & SG

Ligands: enkephalin, deltorphin, DPDPE

Involved in anxiolysis, antidepressant properties, respiratory stimulation or depression, upregulation of brain-derived neurotrophic hormone, cardioprotection, potentiation of mu analgesia

2 subtypes of delta receptor have been characterized. Its role is not well established, but delta receptors are believed to be involved in potentiating mu-receptor analgesia, dependence, and reward.

ORL1 - Orphan Receptor, Opioid-Like-Receptor 1 (OP4)

(Ligand: nociceptin)

hyperalgesia (pain), anxiety, counteraction of mu-agonist effects, anorexia or hunger
Endogenous receptor for nociceptin, the neurotransmitter implicated in transduction of pain signals.

Friday, November 18, 2011

US/Mexico Border Warriors

Drug Warrior Rationale (And its Fundemental Flaws)

I believe this to be a perfect demonstration of the logical or intellectual reductionism at play in promoting "war on drugs".

Popular logic dictates that:

Cartels & gangs traffic drugs. Therefore 'cartels & gangs must = drugs'.

'Drugs' are armed, violent and must be fought.

US heroes (i.e. police & military) must fight war against 'drugs' and 'drug violence'.

What they fail to mention:

Cartels traffic drugs because they are too profitable.

Drugs are too profitable because they are illegal.

Imagine that bananas became illegal tomorrow:

Their value will skyrocket, overnight.

Immediately, violent cartels would then begin trafficking bananas for the enormous profits.

The US would reason that: violent cartels who traffick bananas = 'bananas'.

The US would then be battling an epidemic of 'bananas', 'banana violence' & 'banana crime'.

If the same cartels began leasing out child prostitutes, we would then have a 'banana related prostitution problem'.

Additionally, let's say one of these cartel members gets drunk one night and beats, rapes and kills his wife - Fox news would then have a bloody, brutal, 'banana related murder' to report.

Wednesday, November 16, 2011

Khat Leaf, Cathines, and Cathinones Vault

Catha edulis is a flowering plant which commonly grows in the horn of Africa and the Arabian peninsula. Its leaves are rich with psychoactive alkaloids and are chewed for their stimulating effect. The leafy preparation is popularly known as Khat. 


Cathine is an analogue of amphetamine and a precursor to cathinone. It is the primary naturally occurring alkaloid in "Khat". It differs from amphetamine with the presence of an OH group on the ethyl side chain. It is one optical isomer of phenylpropanolamine. Cathine acts as a sympathomimetic (stimulant) with similar effects to other amphetamines.  


Cathinone is a naturally occurring alkaloid of the substituted amphetamine class. It occurs as an isolated compound or as one of several alkaloids present in the "Khat" plant. It is popularly used for its psychostimulant properties.

Cathinone is chemically described as a substituted phenethylamine. It is a derivative of cathine where the side chain OH group has been oxygenated to a ketone. It is alternatively decribed as a beta keytone of amphetamine.

Its pharmacological profile is similar to amphetamine, both act as sympathomimetics. It acts by triggering an increased synaptic flow of catecholamines centrally and peripherally. Its rewarding & reinforcing effects are due to increased dopaminergic activity at the mesolimbic level.


Methcathinone is to cathinone as methamphetamine is to amphetamine. It is a psychostimulant drug of the substituted amphetamine family. Its sympathomimetic effects are similar to cathinone and methamphetamine; it acts by increasing synaptic concentrations, and thus neurotransmission, of catecholamines, both centrally and peripherally.


Known chemically as 4-methylmethcathinone. Mephedrone is the 4-methyl derivative of methcathinone and has been marketed as a popular research chemical; until being banned in the US in recent months. Its effects are similar to amphetamine and MDMA. Like other amphetamines, mephedrone increases the flow of catecholamines and serotonin throughout central and peripheral circuits, this is mediated by its action at monoaminergic and 5HT (serotonergic) transporters - specifically, it induces neurotransmitter release and inhibits presynaptic reuptake. Following administration of the drug, dopamine levels in the NA are increased up to 500% compared to baseline, while 5HT levels are increased by up to 950%.


Known chemically as 4-methoxymethcathinone. Methedrone is the 4-methoxy derivative of methcathinone. It differs from mephedrone only with the presence of an oxygen linking the 4-ethyl group with the phenyl ring. It has been marketed as a popular research chemical. Like other amphetamines, methedrone increases the flow of catecholamines and serotonin throughout central and peripheral circuits, this is mediated by its action at monoaminergic and 5HT (serotonergic) transporters - specifically, it induces neurotransmitter release and inhibits presynaptic reuptake.


Methylone is a psychostimulant drug of the cathinone-amphetamine family. It possesses stimulant and empathogen properties. Methylone is a 3,4 methylenedioxy analogue of methcathinone, and differs from MDMA with the presence of the side chain ketone. It produces its effects by inducing release/inhibiting reuptake of 5HT and monoamine neurotransmitters. Its empathogenic effects are similar to ecstasy - due to its close structural similarity and its potent serotonergic properties. The drug has been marketed as a research chemical 

Friday, November 11, 2011

Analgesia VS Loss of Sensation: An Important Distinction

I tend to laugh at the idea of someone slapping themselves in the face or pinching an arm to see if the narcotics have kicked in yet. This is actually more common that you might think. For those who don't actually understand the humor in this, I'd like to take a moment to emphasize the difference between opioid induced analgesia and actual anaesthesia.

There are 2 main types of fibers (i.e. neurons) which carry painful stimuli up the spinal cord to the brain, and each carries its own specific type of stimuli.

A-Fibers: carry sharp sudden pain (touching a burning stove, stubbing a toe, hitting a funny bone). These pathways mediate reactive pain which instantly tells the brain that something is wrong and allows a protective reflex to kick in. For instance when you lay your hand on a scalding hot stove, crush your fingers in the car door, stick a fork in an electrical outlet, get kicked in the nuts, or when your girlfriend gets angry and slices your dick off with a box cutter in your sleep - the pain triggers a reflex telling you to pull away, or to scream and cover what's left of your dick with your hands.

Notice that morphine doesn't necessarilly make you immune to sudden reactive pain, but rather dulls any current underlying pain. The closest one will get to "immunity" from sudden pain would be with a high dose of an ultra-potent opioid such as fentanyl. There are actually anecdotal reports of individuals who begin to experience a loss of noxious sensation with acute high doses of fentanyl - indeed, high doses of fentanyl type drugs by themselves can produce complete general anaesthesia (i.e. a full blockage of pain transduction at the dorsal horn). However, anyone taking a high enough dose of fentanyl to experience this is lucky to be alive - No one outside of a hospital-surgical setting should be dosing anywhere near high enough to lose sensation (i.e. "induce anaesthesia"). That's right; anaesthetizing yourself at home is a bad idea.

C-Fibers: carry dull constant pain (headache or toothache, cancer or illness, chronic pain)

Opioids work by targeting ascending C-fibers. They are therefore effective in relieving deep, aching pain - this includes the pain that is felt in the days or weeks following injuries or surgeries, as well as chronic pain experienced following severe injuries or occurring due to a range of conditions.

More SAR

All of the structures included will give a perfect structural overlay - right click @ 'save' image to open in Microsoft Paint. Select image cut & paste mode. Find the 'Selection' box with the arrow underneath (in the upper left corner) - scroll to the bottom of the menu and select "trasparent selection". This allows you to cut and drag one image over the other with a transparent background.

This image demonstrates the similarity between narcotics in their configuration to the Mu receptor. 

This image depicts the morphine backbone along with several opioids in a matching configuration, with the backbone in red. Note the similarities in each molecule. Also note the T-shape of their structures (th morphine-derivatives in particular). The structural characteristics of the more potent opioids emphasize the morphine rule, with enhancements or modifications in the areas most significant to receptor docking & recognition.

Please give due credit if re-publishing this image (Project Narco)

Thursday, November 10, 2011

Nonbenzodiazepines: Drug Information Page

Quick Facts: 

Also known as the 'Z' Drugs or the 'benzodiazepine-like drugs'.

Class of centrally acting depressants with a distinct chemistry but similar pharmacology to the benzodiazepines. Z-drug is to benzodiazepine as opioid is to opiate, (or fentanyl to morphine).

Currently 2 which are widely used in the US - Zolpidem (i.e. Ambien, Ambien CR) and eszopiclone (Lunesta).

Like benzodiazepines, Z drugs target the benzodiazepine subtype of the GABA-a receptor complex, exerting a braking effect on excitatory neuro-transmission and leading to a calming affect on a given portion of the brain.

Limited information exists as to the development of tolerance, dependence, and long term effects of nonbenzodiazepines compared to benzodiazepines. However, one can assume they are similar in these respects.

Z drugs are most often used as prescription sleep aids. They are now often preferred to benzodiazepines in the treatment of insomnia & related sleep disorders.

The first to appear were zopiclone, zolpidem, and zaleplon; all three are used as sleep aids.

Side effects are similar to benzodiazepines and include hypnosis, anterograde amnesia, skeletal muscle relaxation, depression, ataxia and cognitive impairment.

Some Z-drugs have been known to produce bizzarre side effects such as hallucinations or even fugue states; characterized by sleepwalking, talking, driving, cooking and performing other complex tasks while not awake, with no recollection of the events afterward. This has been common with zolpidem in particular and has made Ambien a popular recreational drug in some circles.

Recent research & development has focused on a class of nonbenzodiazepine derivatives for anxiolytic use. These compounds possess anti-anxiety properties of the benzodiazepines and nonbenzodiazepines but produce little to no hypnosis or intoxication at therapeutic doses. For instance, pagoclone binds with benzodiazepine receptors with extreme selectivity, targeting the GABA a2 and a3 subtype without affecting the a1 subtype - the a2 and a3 subtypes mediate the anxiolytic effects of benzodiazepine-type drugs, while the a1 subtype mediates sedation & memory loss.

Benzodiazepine structure (far right) VS Nonbenzodiazepine structure (first 3 on the left)

Wednesday, November 9, 2011

Ketamine: Drug Information Page

Ketamine is an anaesthetic drug of the dissociative type. Produces effects similar to PCP, dextromethorphan, tiletamine and nitrous oxide. Popular for recreational & medical use.

Discovered by Parke Davis Co in the early 1960's as an alternative to their other anaesthetic PCP, which had been associated with neurotoxicity and psychotomimetic side effects - These "bizzarre" side effects may be desireable for recreational drug users, but have been described as terrifying for medical patients, many of whom have complained about these effects once awakened from surgery. Ketamine produces similar effects to PCP at a dose ratio of 4/1 (ketamine/pcp). PCP has been removed from the market (for human use) and replaced with ketamine, which is used in both humans and animals.


Most commonly given in the hospital setting. Low doses produce analgesia while higher doses produce anaesthesia. Ketamine is unique in that with anaesthetic doses it produces stimulation of vital functions rather than depression.

Used as a general anaesthetic/analgesic during surgery, along with other basic components of anaesthesia such as opioid analgesics, sedatives and neuromuscular blocking agents.

Widely used in veterinary medicine as an anaesthetic & analgesic.

Used as a supplement to epidural anaesthesia/analgesia typically by the IV route.

Also given alone or with additional drugs for procedural sedation and emergency analgesia in a field setting (i.e. auto-accidents with trapped subjects & in military combat zones). Its use in trauma is because of its ability to increase or maintain cardiac output, which is especially desireable in cases of blood loss where a subject's blood volume is unknown. It is often preferred in the absence of ventilation equipment due to its lack of respiratory depressant effect.

Ketamine is widely used as a veterinary anaesthetic.

Low doses are useful in relieving neuropathic pain. Low doses may be given as a supplement to narcotics in cases of neuropathic, cancer related, or other forms of severe pain.

Off label or investigational uses include Complex Regional Pain Syndrome and alcohol & opioid addiction.

Observed to be particularly effective in relieving symptoms of refractory major depression. Single parenteral doses of ketamine have been shown to produce significant relief of symptoms within hours of injection, lasting up to a week after injection - This was observed in multiple subjects with major depressive disorder which had consistently failed to respond to other treatments.

Pharmacology & Chemistry

NMDA receptor antagonist, sigma receptor agonist and dopamine reuptake inhibitor. Shows a weak affinity for the mu receptor in high doses. Its binding at the NMDA receptor prevents the binding of the excitatory neurotransmitter glutamate (a positive modulator of ion channel activity), the result being an inhibition of signal transduction in certain areas.

Molecular analogue of PCP. Chemically it is a bicyclic ketone compound with an arylcyclohexylamine core. It is chemically designated ((RS)-2-(2-Chlorophenyl)-2-(methylamino)cyclohexanone).

Racemic compound composed of an (R) enantiomer and an (S) enantiomer. (S)-ketamine has stronger sedative & analgesic properties with 4x greater affinity for the NMDA (PCP-subtype) receptor - (S) is sometimes used as a single isomer product. (R)-ketamine is a stronger sigma agonist than the (S) enantiomer. Actions at the sigma receptor are believed to lower the seizure threshold.


Ketamine is very short acting. Effects generally last 30 to 60 minutes by any route.

Produces dissociative anaesthesia. As such, its effects differ in nature from drugs of the tryptamine or phenethylamine classes, (which could more likely be considered "hallucinogens" in the proper sense). Instead, dissociatives such as ketamine produce a dose dependent separation of the conscious mind from sensory perception of one's body & surroundings, in some cases allowing a user to experience complete depersonalization - characterized by the complete loss of one's sense of identity, unawareness or oblivion to the outer world, and a shockingly realistic experience of alternate realities or dimensions which exist only inside one's brain chemistry - or as some have theorized, a reality which exists outside of space & time or inside one's soul. Some may speculate that such an experience serves as a glimpse of one's reality before existence & birth, or what one might experience after death.

Effects in low to moderate doses include analgesia, excitement, euphoria and altered senory perception. Effects in high doses include sedation, ataxia (trouble walking characterized by robotic leg movements - i.e. the robo-walk), slurred speech, strange utterances or random words, incoherent sentence structure, meaningless gibberish, aphasia (inability to speak), numbness, double vision, profoundly altered state of reality, loss of sensory perception (i.e. mind/body dissociation), complete loss of motor-ability (essentially equivalent to paralysis), out of body experiences, and time dilation. The author can attest to every one of these occurences (but rather with DXM) with the exception of out of body experience. Side effects of ketamine are similar to those of DXM and include hypertension, nausea & vomiting, hypersalivation, and respiratory depression/stimulation.

Effect Summary

The effects of this drug are relatively short lasting. The drug takes effect after anywhere from 1 minute to 10 minutes, depending on the route of administration. Peak effects are experienced at about 20-40 minutes and rarely exceed an hour in duration. This applies to both intranasal and intramuscular use.


Body buzz

Increased energy

Megalomania & changes in ego

Sense of invincibility

Increased self confidence

Dose dependent sedation or stimulation


Dose dependent anaesthesia

Empathy toward others & increased sociability

Distortion and loss of sensory perceptions (dose dependent)

Closed eye or open eye visuals

Intense body buzz

Complete mind/body dissociation in high doses (very bizarre)

Distorted perceptions of reality or loss of self awareness


Slurred speech

Out of body experience

Distorted time perception

Ataxia and impaired motor coordination

Increased heart rate or depression of heart rate, respiratory depression, nausea & vomiting

Depressant Drugs: Overview

Overview of the Depressant Drugs

Mind altering depressant drugs are a broad category of compounds which act on the central nervous system (CNS). Unlike the excitatory role of stimulants, depressants play an inhibitory role on neurotransmission within the CNS, particularly at the brain and spinal cord level. The inhibitory effects of depressants are mediated through different mechanisms; Most traditional depressant drugs, namely barbiturates and benzodiazepines, produce inhibition by one or both of the following means; A) agonism of an inhibitory receptor, or B) antagonism of an excitatory receptor.

GABA receptors mediate inhibition of the central nervous system; and bind the natural neurotransmitter gamma-aminobutyric acid, a GABA agonist. These receptors play a braking role on the nervous system, by slowing or stopping the firing of other neurotransmitters. Activation of GABA receptors at post synaptic sites inhibits the transduction of the neurotransmission which it receives, while activation of presynaptic GABA receptors inhibits neurotransmission into the synaptic cleft and on to the post synaptic neuron. GABA activity at both pre and post synaptic sites leads to a decrease in function of a particular visceral, brain, or spinal area. GABAergic drugs play many roles in therapy and recreation, generally for their anxiolytic, sedative, hypnotic, amnesic, and emotional-blunting effect.

GABA is not the only means of inhibitory transmission. CNS inhibition is acheived with the use of an NMDA receptor antagonist. NMDA receptors rely on the binding of two main neurotransmitters, N-methyl-D-aspartate and glutamate. The NMDA receptor serves the functional role of a gatekeeper of neurotransmission; its activation via NMDA agonists allows the neuro-channels to open, thus allowing the flow of transmission throughout the brain and spinal cord. Therefore, by blocking the NMDA receptor with the use of an NMDA antagonist drug, the "gate" becomes closed; blocking this flow of neurotransmission. This blocking of excitatory function results in an overall inhibition of function in a particular area; visceral, spinal, or brain.

CNS Depressants are widely used in medicine to control; acute anxiety and panic, hypertension and muscle spasms, convulsions or epileptic disorders, as well as pain and isomniatic sleeping disorders. Depressant drugs are often used as general anaesthetics in the surgical setting.

Traditional Depressants (By Pharmacological Class)

Barbiturates - GABA agonist

Benzodiazepines - GABA agonist

Alcohol - GABA agonists, NMDA antagonist, nACh antagonist

Ether - GABA agonist

Dissociative Anaesthetics - NMDA antagonist, Sigma agonist

Volatile Anaesthetics - GABA agonist

In low to moderate doses, classical depressants inhibit cognitive functions of the higher cortical areas, including intelligence, reasoning & judgement, while progressing with higher doses to inhibit sensory perception and motor coordination. With increasing doses generally comes further inhibition of increasingly vital functions.

As doses progress, depressants begin to affect the autonomic nervous system, causing an inhibition of sympathetic "arousal" - including the sympathetic "fight or flight" response to stress; characterized by physiological symptoms of panic or anxiety. Benzodiazapines are used in therapy for this purpose, and are effective in treating acute symptoms of anxiety or panic. Casual use of alcohol produces the same effect. In a much greater capactiy, this additionally proves useful in anaesthesia - An adequate degree of sympathetic inhibition will block the visceral response of the body (response of the organs) to stress, in this case being the pain of surgery. GABA agonist or NDMA antagonist drugs are classically used as general anaesthetics. Benzodiazapines, barbituates, or volatile ethers may be used as general anaesthetics, as well as the NMDA antagonist ketamine. One of the earliest volatile anaesthetics to be used was diethyl ether, a highly potent relative to ethyl alcohol, which has since been replaced by halogenated ethers such as the 'fluranes'. Even alcohol in blood concentrations greater than 0.4 may produce deep anaesthesia adequate for surgery.

Care must be taken; Given in excess, depressant drugs will inhibit autonomic functions completely; meaning respiratory depression, respiratory arrest, heart failure, cardiac arrest, brain death or coma, and death. Excessive doses of benzodiazepines, barbiturates, and even alcohol, will effectively put your brain stem to sleep.

Depressant drugs may act through other mechanisms aside from GABA and NMDA receptors. CNS depression is achieved with the use of anticholinergics, first generation antihistamines, or adrenergic (a2 receptor) antagonists. Ethyl alcohol exhibits additional activity as an NAcH antagonist. Older antihistamines such as diphenhydramine have sedative-hypnotic qualities, while adrenergic antagonists such as beta blockers or clonidine inhibit the sympathetic response to stress and anxiety, causing a physiologically calming effect (often useful in opioid withdrawal or panic attacks).

Depressants drugs for recreational use may fall into several categories, and generally target GABA, GABA receptors, and/or NMDA receptors, Kappa receptors, or Sigma receptors for their pharmacological effects. Alcohol is undoubtedly the most widely used depressant, and most popular recreational drug throughout the world, while other depressants are available in either pharmaceutical form, or clandestinely manufactured illicit form.

Are Opioids Depressants?

Opioids are often classified as CNS depressants, though they are more of a borderline case, and in moderate doses do not produce the typical cognitive/psychomotor impairing effects of a "downer". While typical opioid agonists inhibit certain pathways at the spinal level, they paradoxically produce excitation at the mesolimbic level; inhibiting GABA's braking effect on mesolimbic dopamine firing thus increasing dopaminergic firing and exciting the brain's "pleasure centers". Their subjective effects in a given setting will determine their functional role; low or moderate doses may produce euphoria and excitement without psychomotor or cognitive impairment, observed clinically an improvement in function; while high doses may produce increasing sedation & respiratory depression or in some cases, deep anaesthesia.

Dextromethorphan (DXM): Drug Information


DXM is a synthetic morphinan analogue. It is a member of the opioid molecular class but produces no clinically significant opioid effects. DXM was first synthesized in the search of an antitussive with the efficacy of codeine but with lower liability for abuse and dependence. It acts centrally on the cough center in the medulla and nucleus tractus solaris to increase the coughing threshhold, and is one of the most widely used non-prescription medications in the US.


Robitussin cough gelcaps each containing
15mg of dextromethorphan hydrobromide
Originally marketed as a codeine substitute for over the counter antitussiv use, DXM prodiuced no narcotic effect. However, it was soon found to have a higher "abuse" potential than codeine in the recreational sense.

When used in doses exceeding the therapeutic range of 15 to 60mg, it acts as a dissociative anaesthetic drug, producing the effects of ketamine and PCP. These effects become apparent in doses upward of 200mg and occur non linearly, in dose dependent phases or "plateaus" with increasing dose - of which there are four.

Dextromethorphan has proven useful as an adjunct to opioid therapy from chronic pain. Clinical experience has shown that a 1/1 ratio of dextromethorphan to morphine taken on a regular schedule provides superior analgesia to morphine alone, while attenuating development of morphine tolerance. Dextromethorphan may be used for this purpose as an adjunct to any typical opioid. DXM is taken by recreational opioid users with similar results - i.e. a reduced development of opioid tolerance. It may additionally enhance the euphorigenic effects of opioids.

Moderate doses of dextromethorphan (100 to 300mg/day) have been useful in relieving the discomfort of narcotic withdrawal. Its dissociating or numbing effect has been useful in attenuating both physical & psycho symptoms of the abstinence syndrome. DXM is also effective in reducing the psychological 'cravings' in chronic, post-detoxified opiate users experiencing the depressive symptoms of 'post acute withdrawal syndrome' (or simply, the raw misery of sober life) - owing to its monoaminergic & catecholaminergic properties.


DXM is molecularly similar in structure to codeine. It is a synthetic compound of the morphinan series. It is the dextrorotatory isomer of the methyl ether of levorphanol, and may be considered a methylated right handed analogue of levorphanol.

DXM is a psychoactive drug of the dissociative anaesthetic therapeutic class. This class includes phencyclidine (PCP or angel dust) and Ketamine (or 'special k'). Drugs of this type are used therapeutically and recreationally to induce a dissociation of the conscious mind from one's body and environment. This is caused by the partial to complete inhibition of sensory input to the conscious mind. This has made such agents useful is surgical or emergency anaesthesia, although their use is less common in humans as it is in animals, due to the bizzarre states of consciousness which have frightened many patients (apparently cats and dogs have not yet reported these effects, much less expressed any complaints)

DXM is a seretonin reuptake inhibitor, a PCP2-receptor agonist, and a sigma receptor agonist. In the higher dose range, DXM is a low efficacy NMDA receptor antagonist - its major metabolite, dextrorphan, is a far more potent NMDA antagonist, and accounts for most of the activity at this site. Activity at NMDA and PCP2 receptors causes dopamine reuptake inhibition in the nucleus accumbens, lending to its euphoric, exciting, stimulant like effects in lower doses (1.5-2.5mg/kg). The effects of the drug are mediated via both dextromethorphan & its major metabolite dextrorphan.

Activity of the NMDA receptor in the simplest of terms, allows for the communication of signals between neurons and the brain; when NMDA receptors are active or "open" (which requires binding of glutamate), they allow neurons to transfer signals freely.

Many dissociative agents share similar pharmacological properties, acting as antagonists to the NMDA receptor; by a variety of means - the intricate workings of NMDA mechanisms is quite complex. Their purpose is to mediate the polarization of cellular channels which allow the transfer of signals between neurons. The NMDA receptor essentially works as a gatekeeper at the post-synaptic membrane. Activation of an NMDA receptor keeps channels open, while inhibition of NMDA receptors causes channels to close; the blocking of the post synaptic NMDA ion channel inhibits the potential of the nerve cell to fire upon receiving synaptic neurotransmission (from the axon terminals of another neuron).

The dose dependent pharmacology of DXM can be summarized as follows:

Low Doses (1st Plateau) - PCP2 mediated increase in dopaminergic tone
Moderate Doses (2nd and 3rd Plateau) - Sigma agonism, PCP1 mediated NMDA blockade
High Doses (4th Plateau) - PCP1 mediaterd NMDA blockade

Effects and Side Effects:

Dopaminergic effects of DXM are most prominent in the lower range of recreational doses. DXM blocks the reuptake of dopamine by its action at the PCP2 receptor site, located on the surface of the dopamine reuptake complex. Increased synaptic dopamine in the VTA and nucleus accumbens produces euphorigenic & reinforcing effects. Dextromethorphan in this dose range, also known as the first plateau, produces an invigorating state of pleasure similar to stimulants such as cocaine. Auditory stimulation such as music is extremely pleasant, while motor stimulation such as movement (walking, dancing, etc) is desireable as well. As doses progress, PCP2 mediated dopaminergic effects begins to plateau.

In midrange doses, often known as the second plateau, sigma activity is more pronounced. There is increasing alteration of sensory perception and memory. Brain-motor coordination is affected, leading to a robotic-like movement of arms and legs which is especially apparent when walking. the sensation may be described as attempting to walk in zero gravity, and struggling for one's feet to touch the ground. Psychotomimetic (psychotic-like) effects may be present at this dose. Antagonism at NMDA & sigma receptors impairs the mediating of memory and the brain's ability to coordinate communication between conscious mind and data storage sites in the brain - one has no sense of time, and is often able to perform repetitive or mundane tasks without becoming bored; this may include staring at a wall, or masturbation (joking. jacking off while tripping might be dangerous). Abstract or bizzarre though patterns may become obvious to others, while the user may not perceive it this way. Inhibition of sensory input begins at this level, marked by choppy communication from the body and senses to the brain - Events may be perceived in the mind seconds or minutes after they happen, or may not be experienced at all. One may experience tunnel vision, and perceive ones self as something or someone else, while struggling to understand "what one's environment actually is" - defined best as the complete loss of ones awareness of the nature or existence of one's environment or "existence" in general.

In much higher doses, most effects of the experience are mediated solely by NMDA antagonism and its subsequent sensory inhibition. Specifically, DXM binds to the PCP1 site located on the interior surface of the NMDA ion channel complex (this is the source of its NMDA antagonistic action). Perhaps the most bizzare effect at this dose level are the increasing gaps in sensory input; this means literally what it sounds like - all physical and environmental perception experiences cut-offs; the best way to describe this experience is simply; an irregular and bizzare state of consciousness where rather than awareness of one's body or environment, there is awareness of nothing; this may be experienced as a complete 'white out' phase, or the complete loss of self awareness. This may be accompanied by strange, disconnected behavior, or a complete incapacity for motor movement and speech.

"What I can say is that when I came to while being examined is that I was so thoroughly saturated with DXM that I cannot imagine going higher on DXM. I did not know what I was. I only knew that I was something taking in images. As I was slid from gurney to gurney, I started to become aware that I existed. My ego had coalesced. I saw people around me and I had an urge which translated to a desire to talk after some period of time. Unfortunately, I did not know how to talk at that point. I went in and out of consciousness into the evening. I felt euphoric and thought I was a god in my conscious moments." - DXM User (Erowid.org)

Further Off-Site Reading: A chronic user recollects his experiences with high dose DXM (Erowid)

Tuesday, November 8, 2011

GHB Vault

i.e. Gamma-hydroxybutyric-acid or sodium oxybate

GHB is a sedative hypnotic drug which also occurs naturally in the human central nervous system. It is used both medicinally and as a recreational drug. GHB is approved for clinical use in the US as a treatment for cataplexy associated with narcolepsy, and has been popularly termed "the date rape drug". It is sold under the trade name Xyrem.

GHB is a potent central nervous system depressant with hypnotic, amnestic, muscle relaxant, anticonvulsant, and anaesthetic properties.

It is an analogue of the inhibitory neurotransmitter GABA (chemically, gamma-aminobutyric-acid, and shares similar pharmacology. GHB acts as an agonist at the newly discovered GHB receptor, and a weak agonist at the inhibitory GABA-b receptor - The GABA-b receptor differs from the GABA-a subtype (a ligand gated ion channel), in that it is a G-protein coupled receptor.